Evaluation of the transgenic p53(+/-) mouse for detecting genotoxic liver carcinogens in a short-term bioassay

The transgenic p53-deficient heterozygous (p53(+/-)) mouse is prone to both spontaneous and induced tumors and has been proposed for use in a sensitiv e, short-term (6 months) assay for identifying genotoxic, multispecies carc inogens. It is not clear, however, if a short-term assay with p53(+/-) mice detects agents that target certain organs, in particular, the liver. In th is study, we treated neonatal male p53(+/-) and p53(+/+) mice with the geno toxic carcinogens dimethylnitrosamine (DMN), 2-amino-1-methyl-6-phenylimida zo [4,5-b]pyridine (PhIP), and 6-nitrochrysene (6-NC). In keeping with the methodology of the proposed short-term assay, the p53(+/-) mice were evalua ted for tumors 7 months after treatment. Wild-type neonatal mice treated wi th genotoxic carcinogens are known to develop tumors within 1 year; hence, the p53 (+/+) animals used as controls were subjected to pathological exami nation at 1 year of age. Our results showed that PhIP was not tumorigenic i n either group of mice. Liver tumor incidence increased significantly in th e p53(+/+) mice treated with DMN and 6-NC, indicating that the conditions o f the bioassay were conducive to the promotion of liver tumorigenesis. On t he other hand, these two chemicals failed to induce a significant increase in liver tumors in the p53(+/-) mice by seven months. This result suggests that a deficiency in the amount of p53 protein does not lead to accelerated liver tumorigenesis in mice, and contrasts with previous reports that show a decreased latency of tumors in non-liver targets. (C) 1999 Elsevier Scie nce Ireland Ltd. All rights reserved.